Krämer A, Frank H, Setiabudi F, Oesch F, Glatt H
Institute of Toxicology, University of Mainz, Federal Republic of Germany.
Biochem Pharmacol. 1991 Nov 6;42(11):2147-52. doi: 10.1016/0006-2952(91)90350-e.
trans-beta-Ethylstyrene 7,8-oxide, a substrate of cytosolic epoxide hydrolase, and 4-fluorochalcone oxide, an inhibitor of this enzyme, were investigated on induction of sister chromatid exchanges (SCE) in human lymphocytes. Both epoxides enhanced the frequency of SCE. 4-Fluorochalcone oxide at low concentration (2.5 microM) inhibited cytosolic epoxide hydrolase activity towards trans-beta-ethylstyrene 7,8-oxide in lymphocytes by 74% and had no effect on glutathione transferase activity using this substrate. At this concentration it did not induce SCE itself, but it potentiated the effect of trans-beta-ethylstyrene 7,8-oxide several fold. In lymphocytes from different subjects, the number of SCE induced by a low concentration of trans-beta-ethylstyrene 7,8-oxide correlated negatively with the individual cytosolic epoxide hydrolase activity (r = -0.72; -0.73 in two series of experiments). The number of SCE induced by a high concentration of trans-beta-ethylstyrene 7,8-oxide did not correlate with cytosolic epoxide hydrolase activity (r = 0.004; -0.24), but a negative correlation was found with glutathione transferase activity (r = -0.50). This finding is consistent with the results of biochemical studies in lymphocytes in which we determined the relative contribution of cytosolic epoxide hydrolase and glutathione transferase to the metabolism of trans-beta-ethylstyrene 7,8-oxide at varying substrate concentrations. The study demonstrates that the level of genotoxic effects induced in human lymphocytes is influenced by the individual level of detoxifying enzymes. At low concentrations, cytosolic epoxide hydrolase was more important than glutathione transferase activity.
反式-β-乙基苯乙烯7,8-氧化物，一种胞质环氧化物水解酶的底物，以及4-氟查尔酮氧化物，该酶的一种抑制剂，被用于研究对人淋巴细胞姐妹染色单体交换（SCE）的诱导作用。两种环氧化物均提高了SCE的频率。低浓度（2.5微摩尔）的4-氟查尔酮氧化物可使淋巴细胞中胞质环氧化物水解酶对反式-β-乙基苯乙烯7,8-氧化物的活性抑制74%，且对使用该底物的谷胱甘肽转移酶活性无影响。在此浓度下，它本身不诱导SCE，但能使反式-β-乙基苯乙烯7,8-氧化物的作用增强数倍。在来自不同受试者的淋巴细胞中，低浓度反式-β-乙基苯乙烯7,8-氧化物诱导的SCE数量与个体胞质环氧化物水解酶活性呈负相关（在两个系列实验中r分别为-0.72和-0.73）。高浓度反式-β-乙基苯乙烯7,8-氧化物诱导的SCE数量与胞质环氧化物水解酶活性无相关性（r = 0.004；-0.24），但与谷胱甘肽转移酶活性呈负相关（r = -0.50）。这一发现与淋巴细胞生化研究结果一致，在该研究中我们确定了在不同底物浓度下胞质环氧化物水解酶和谷胱甘肽转移酶对反式-β-乙基苯乙烯7,8-氧化物代谢的相对贡献。该研究表明，人淋巴细胞中诱导的遗传毒性效应水平受解毒酶个体水平的影响。在低浓度时，胞质环氧化物水解酶比谷胱甘肽转移酶活性更重要。
